1. Description of Related Art
Active drugs often have undesirable side effects at their therapeutically effective concentrations. This is particularly problematic for topical use in sensitive areas such as the eyes, where irritation is very difficult to avoid even for relatively mild drugs. As a result, formulating topical ophthalmic drugs is a particularly challenging problem. This is unfortunate because topical ophthalmic use of drugs has been found to be very useful in managing many conditions affecting the eye such as dry eye, infection, inflammation, allergy, and glaucoma. Glaucoma is a particularly devastating disease of the eye characterized by increased intraocular pressure, which is often treated by topical ophthalmic application of a drug. Glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision. In cases where surgery is not indicated, many drugs have been found to be useful in treating glaucoma by topical application including β-adrenoreceptor antagonists and α2-adrenoreceptor agonists. Recently, prostaglandins have been shown to be particularly useful in the topical treatment of glaucoma.
Whereas prostaglandins appear to be devoid of significant intraocular side effects, ocular surface (conjunctival) hyperemia, foreign-body sensation, and itching (pruritus) have been consistently associated with the topical ocular use of such compounds, in particular PGF2α and its prodrugs, e.g., its 1-isopropyl ester, in humans. The clinical potentials of prostaglandins in the management of conditions associated with increased ocular pressure, e.g. glaucoma are greatly limited by these side effects.
U.S. Pat. No. 5,688,819, commonly assigned to Allergan, Inc., and incorporated herein by reference discloses that derivatives prostaglandins known as prostamides, wherein the carboxylic acid group is replaced by an amide substituent have pronounced effects on smooth muscle and are potent ocular hypotensive agents. Additionally, prostamides cause significantly lower ocular surface hyperemia than the parent compounds. One prostamide exemplary of the these effects is bimatoprost, which is marketed by Allergan, Inc. under the trade name Lumigan®, which has the structure shown in Formula I below. However, although bimatoprost is associated with significantly less hyperemia and other irritating side effects compared to certain prostaglandins, further improvement is still highly desirable.
Cyclodextrins are cyclic oligosaccharides containing 6, 7, or 8 glucopyranose units, referred to as α-cyclodextrin (structure depicted below), β-pharmaceutical or γ-cyclodextrin respectively, which are often used in pharmaceutical formulations. Cyclodextrins have a hydrophilic exterior, which makes them water soluble, and a hydrophobic interior which forms a cavity. In an aqueous environment, hydrophobic portions of molecules often enter the hydrophobic cavity of cyclodextrin to form inclusion compounds. Although inclusion compounds are often formed between cyclodextrins and hydrophobic molecules, cyclodextrins are also capable of other types of noncovalent (nonbonding) interactions with molecules that are not inside the hydrophobic cavity. Cyclodextrins have three free hydroxyl groups for each glucopyranose unit, or 18 hydroxyl groups on α-cyclodextrin, 21 hydroxyl groups on β-cyclodextrin, and 24 hydroxyl groups on γ-cyclodextrin. One or more of these hydroxyl groups can be reacted with any of a number of reagents to form a large variety of cyclodextrin derivatives. Some of the more common derivatives of cyclodextrin are hydroxypropyl ethers, sulfonates, and sulfoalkylethers.
In pharmaceutical formulations, cyclodextrins and cyclodextrin derivatives are often used to improve the solubility of an active drug. In many cases, it is believed that inclusion compounds formed between a cyclodextrin or cyclodextrin derivative and a lipophilic drug are important to the enhanced solubility observed. The lipophilic portion of the drug is enclosed in the cyclodextrin cavity forming favorable hydrophobic interactions with the inside of the cavity, and also reducing or eliminating the unfavorable interactions between water and the hydrophilic interior of the cavity and water and the hydrophobic drug. While inclusion compounds are involved in many cases of enhanced solubility, other interactions between cyclodextrins and insoluble compounds can also improve solubility. As mentioned, the use of cyclodextrins in pharmaceutical compositions is well known in the art. For example, U.S. Pat. No. 6,407,079 teaches the use of cyclodextrin derivatives to form inclusion compounds that improve the solubility of the active drug. EP 579435 teaches the use of cyclodextrin or a cyclodextrin derivative and a water soluble polymer to solubilize or stabilize an active drug. The use of cyclodextrin and cyclodextrin derivatives in ophthalmic formulations is also well known. For example, European Patent Application 0435682 A2 teaches the use of cyclodextrins in ophthalmic compositions with prostaglandins to treat ocular hypertension. Generally, these complexes are formed in such a way that the formulation is saturated with the active drug. For example, the mixture is heated to dissolve, cooled, and the remaining solid drug removed via centrifugation or filtration. However, it is not taught in the art that the use of cyclodextrin or cyclodextrin derivatives at concentrations significantly beyond that needed to solubilize or stabilize the active drug should have additional benefits. Rather, one would expect that increasing the amount of cyclodextrin in the formulation beyond that required to solubilize the drug would increase the amount of drug complexed to the cyclodextrin, which might significantly impair the bioavailability of the drug, reducing the effectiveness of the formulation.